Process for the preparation of cinnamic acid derivatives

ABSTRACT

The invention relates to a process for the preparation of cinnamic acid derivatives which involves reacting chlorinated aromatic compounds and acrylic acid derivatives in the presence of palladium catalysts.

The present invention relates to a process for the preparation ofcinnamic acid derivatives.

It is already known that olefins can be arylated by bromoaromaticcompounds in the presence of palladium catalysts, phosphine ligands anda base (see R. F. Heck, Org. React. 27, 345-391 (1982)).

According to Y. Ben-David et al., Organometallics 11, 1995 (1992) thearylation of alkenes using chloro-aromatic compounds can only be carriedout in the presence of bidentate phosphine ligands.

The reaction is frequently carried out with various amines (e.g.triethylamine, tributylamine, tetramethylethylenediamine), which mayserve simultaneously as solvent. The bases employed may include alkalimetal carboxylates in dimethylformamide (see EP-A 78 768) or alkalimetal carbonates or hydrogen carbonates, given the simultaneous presenceof a polar aprotic solvent (e.g. dimethylformamide, hexamethylphosphorictriamide, acetonitrile) and a phase transfer catalyst (see TetrahedronLett. 26, 2667-2670 (1985) and J. Org. Chem. 56, 1289-1293 (1991)).

Furthermore, the patent application WO 90/10617 discloses that, in atwo-step process, p-methoxyaniline (=p-anisidine) can first of all bediazotized, and then the product can be converted using potassium iodideinto 4-iodanisole. This product can subsequently be reacted with2-ethylhexyl acrylate, in the presence of triethylamine and a palladiumcatalyst, to give 2-ethylhexyl 4-methoxycinnamate. This process involvesa large number of steps and requires the recovery of alkali metaliodide.

The reaction of 4-iodoanisole with methyl acrylate and a stoichiometricquantity of tetramethyl-ethylenediamine in the presence of 1 mol% ofpalladium(II) acetate results, after 5 hours at 100° C., in a yield ofonly 68% of methyl 4-methoxycinnamate (J. Org. Chem. 37, 2320-2322(1972)).

The reaction of 4-bromoanisole with methyl acrylate and a stoichiometricquantity of tetramethyl-ethylenediamine in the presence of from 1 to 2mol% of palladium(II) acetate and 2 to 4 mol% of triphenyl-phosphinegives, after 36 hours at 135° C., a yield of methyl 4-methoxycinnamateof 54% (J. Am. Chem. Soc. 96, 1133-1136 (1974)).

DE 42 11 608 proposes the reaction of bromoaromatic compounds withacrylic acid derivatives in the presence of palladium catalysts and alarge excess of phosphines, based on palladium. The phosphine producedin relatively large quantities in this reaction creates additionaldifficulties in isolating the product.

EP 0 509 426 describes the preparation of octyl p-methoxycinnamate fromp-bromoanisole and octyl acrylate in the presence of a base and of acoupling catalyst in a polar aprotic solvent. All of the processes whichhave been disclosed to date produce bromide salts as by-products,resulting in a considerable pollution of the waste water or in alaborious recovery procedure. None of the processes known to date has asuccessful outcome with the corresponding chlorine derivative.

EP 103 544 describes a process for the arylation of acrylonitrile withp-chlorobenzaldehyde in the presence ofchloro(4-formylphenyl)bis(triphenyl-phosphine)palladium(II), the productbeing obtained in a yield of only 18%.

There is therefore a need for a process which can be used to react thechloroaromatic compounds, which are less reactive but easier to prepare,in the presence of palladium catalysts with acrylic acid derivatives inhigh space-time yields and without the use of auxiliaries requiring anyparticular complexity.

A process has now been found for the preparation of cinnamic acidderivatives from chloroaromatic compounds and acrylic acid derivativesin the presence of palladium catalysts and a phosphine, which process ischaracterized in that a lipophilic, aliphatic phosphine is employed ofthe formula I ##STR1## in which R¹ at each occurrence independently ofone another is straight-chain or branched C₁₋₆ -alkyl, C₁₋₆ -alkoxy,C₄₋₈ -cycloalkyl or C₄₋₈ -cycloalkoxy, preferably branched C₃₋₆ -alkyl,C₃₋₆ -alkoxy or cyclohexyl, and

R² is straight-chain or branched C₁₋₆ -alkyl, C₁₋₆ -alkoxy, C₄₋₈-cycloalkyl or C₄₋₈ -cycloalkoxy or a radical of the formula II ##STR2##in which R³ is divalent C₁₋₂₀ -alkylene, and

R¹ is as defined above.

The quantity of palladium can be chosen such that, based on thechloroaromatic compound employed, its proportion is from 0.0001 to 1mol%, preferably from 0.005 to 0.05 mol%.

The acrylic acid derivatives employed may, for example, be those of theformula (III): ##STR3## in which R is CN or COR⁴, where R⁴ is OH, O--C₆--C₁₀ -aryl, O--C₁ --C₂₀ -alkyl, NH₂, NH--C₆ --C₁₀ -aryl, NH--C₁₋ C₂₀-alkyl, N--C₆ --C₁₀ -aryl, N--C₁ --C₂₀ -alkyl-C₆ --C₁₀ -aryl or N-di-C₁--C₂₀ -alkyl, and

R' is H, C₁ --C₂₀ -alkyl, C₆ --C₂₀ -aryl or R.

In the formula (III) R is preferably COR⁴ with R⁴ =O--C₁ --C₂₀ -alkyl,particularly preferably O--C₁ --C₁₀ -alkyl and, in particular,2-ethylhexyloxy. Chloroaromatic compounds which can be employed are, forexample, chlorobenzenes of the formula (IV) ##STR4## in which R⁵ is C₆--C₁₀ -aryl, C₁₋₂₀ -alkyl, CN, S--R⁶, CO--OR⁶, --F, --OCF₃, OR⁶ or NR⁶ ₂where R⁶ is hydrogen, C₆ --C₁₀ -aryl or C₁₋₂₀ -alkyl,

m is 0 or 1,

n is 1 to 5, and

n+m is 1 to 5.

In the formula (IV) R⁵ is preferably OR⁶ or NR⁶ ₂ where R⁶ =phenyl orC₁₋₁₀ -alkyl; R⁵ is particularly preferably methoxy. m is preferably 0,and n is preferably 1.

The molar ratio of chloroaromatic compound to acrylic acid derivativecan be chosen as desired. Preference is given to working at a molarratio of chloroaromatic compound to acrylic acid derivative which is inthe range from 1:0.7 to 1:3. With particular preference this ratio isfrom 1:0.8 to 1:1.5.

Generally, in the case of dichlorobenzene derivatives (m=1), double thequantity of acrylic acid derivative is employed.

Suitable inorganic bases for the process according to the invention are,for example, alkali metal and alkaline earth metal salts of weak acids,preferably alkali metal and alkaline earth metal hydrogen carbonatesand/or carbonates. Particular preference is given to the use of sodiumcarbonate. The ratio of chloroaromatic compound to base is preferablychosen such that from 0.3 to 2, particularly preferably from 0.4 to 1.3,equivalents of base are employed per mole of chloroaromatic compound.

The lipophilic, aliphatic phosphine ligands of the formula I areobtainable commercially or can be prepared in analogy to processes whichare known per se.

In the preferred monodentate phosphine ligands of formula I the radicalsR¹ and R² are identical and have a branched alkyl or alkoxy group or acyclohexyl group.

Accordingly, preferred monodentate phosphine ligands are:trimethylphosphine, triethylphosphine, tripropylphosphine,triisopropylphosphine, tributylphosphine, tricyclohexylphosphine,trimethyl phosphite, tripropyl phosphite, triisopropyl phosphite,tributyl phosphite and tricyclohexyl phosphite, in particulartriisopropylphosphine or tricyclohexylphosphine.

In the preferred bidentate phosphine ligands of formula (I) the radicalsR¹ are in each case identical, and R² is a radical of formula (II) inwhich R³ is preferably divalent C₂₋₆ -alkylene.

Accordingly, preferred bidentate phosphine ligands are:1,2-bis(dimethylphosphine)ethane, 1,2-bis(diethyl-phosphine)ethane,1,2-bis(dipropylphosphine)ethane, 1,2-bis(diisopropylphosphine)ethane,1,2-bis(dibutyl-phosphine)ethane, 1,2-bis(dicyclohexylphosphine)ethane,1,3-bis(dicyclohexylphosphine)propane,1,3-bis(diisopropylphosphine)propane,1,4-bis(diisopropylphosphine)butane and2,4-bis(dicyclohexylphosphine)pentane.

Phosphines can be employed in the process according to the invention,for example, in a molar ratio of palladium:phosphorus of from 1:0.8 to1:2.5. This ratio is preferably from 1:0.9 to 1:2.3 and particularlypreferably about 1:2.

It is self-evident that the ratios indicated relate to the monodentatephosphines of the formula I; in the case of the bidentate phosphines thepalladium:phosphine ratios generally employed are from 1:0.4 to 1:1.25.

The process according to the invention can be carried out, for example,at temperatures in the range from 50° to 180° C. Preferred temperaturesare in the range from 80° to 150° C., and with particular preference arein the region of the boiling point of the solvent employed. The processaccording to the invention is usually carried out at atmosphericpressure. However, it can also be carried out at reduced or elevatedpressure. The application of elevated pressure is particularlyappropriate when it is desired to work at a reaction temperature atwhich individual components of the reaction mixture would boil atatmospheric pressure.

The process according to the invention is generally carried out under aprotective gas, for example nitrogen, and with stirring.

Suitable solvents are hydrocarbons such as, for example, toluene, etherssuch as tetrahydrofuran, polar aprotic solvents such as, for example,N-methyl-pyrrolidone, dimethylformamide, N,N-dimethylacetonitrile ordimethyl sulfoxide.

Using the process according to the invention it is possible, forexample, to prepare cinnamic acid derivatives of the formula (V)##STR5## in which the symbols used have the meaning indicated in thecase of the formulae (III) and (IV).

After the process according to the invention has been carried out, theinorganic salts formed can be separated off, for example, by simplefiltration, with or without suction. It is also possible to leave thesalts to settle and to decant the rest of the reaction mixture.

One possible embodiment of the process according to the invention isdescribed below by way of example of the reaction of 4-chloroanisolewith 2-ethylhexyl acrylate:

trialkylphosphine and palladium(II) chloride are added in a molar ratioof palladium:phosphorus of 1:2 to an initial charge of 4-chloroanisole,2-ethylhexyl acrylate, sodium carbonate and N-methylpyrrolidone (NMP).The sequence of addition of these components can be altered as desired.The mixture is then heated at 140° to 150° C. under nitrogen and withvigorous stirring. After it has been determined that no further4-chloroanisole is reacting, the reaction is terminated: that is, thereaction mixture is cooled to room temperature and poured into water.The aqueous phase is then separated off and extracted with an organicsolvent (e.g. methyl tert.-butyl ether (MTB)). The combined extractsobtained are freed from the solvent and distilled in vacuo.

It is surprising that the palladium-catalyzed therefor reaction,according to the invention, of relatively unreactive chloroaromaticcompounds with acrylic acid derivatives, with the use of very smallquantities of palladium catalyst having a phosphorus ligand of theformula I, gives high space-time yields.

The process according to the invention makes it possible to preparecinnamic acid derivatives, especially 2-ethylhexyl p-methoxycinnamateand isoamyl 4-methoxy-cinnamate, under advantageous reaction conditions,with no particular expenditure being necessary for the handling ofauxiliaries (bases, solvents). The bases, solvents and phosphinesrequired are readily accessible and inexpensive.

The process according to the invention is significantly more economicaland, in comparison with the processes of the prior art, achieves ahigher space-time yield.

Cinnamic acid derivatives, especially the 2-ethylhexyl and isoamylesters of p-methoxycinnamic acid, can be employed, for example, as UVabsorbers in cosmetics (see U.S. Pat. No. 5,008,100 and U.S. Pat. No.4,810,490).

EXAMPLE 1

24.8 ml of 4-chloroanisole, 52.3 ml of 2-ethyl-hexyl acrylate, 10.6 g ofsodium carbonate and 200 ml of NMP are placed in a four-neckedround-bottomed flask, and 2.3 mg of tricyclohexylphosphine and 0.9 mg ofpalladium acetate (2.0 mol% based on 4-chloroanisole) were added. Themixture was heated at 140°-150° C. under nitrogen and with stirring.After 60 hours the conversion according to gas chromatography was 68%,based on the 4-chloroanisole employed.

The mixture is cooled and poured into water. After extraction with 3×200ml of MTB ether, the organic phase formed by combination of the extractsis washed with water, dried over sodium sulfate and filtered. Afterremoval of the solvent the filtrate is distilled under reduced pressure.The yield of isolated 2-ethylhexyl p-methoxycinnamate is 14.5 g.

EXAMPLE 2 (COMPARISON EXAMPLE)

The procedure of Example 1 was followed, but adding 2.1 g oftriphenylphosphine. After 60 hours the conversion according to gaschromatography was 0.5%, based on the 4-chloroanisole employed.

EXAMPLE 3

The procedure of Example 1 was followed, but adding 1.5 mg oftriisopropylphosphine instead of tricyclohexylphosphine. After 60 hoursthe conversion according to gas chromatography was 65%, based on the4-chloroanisole employed.

We claim:
 1. A process for the preparation of a cinnamic acid compoundwhich comprises reacting a chloroaromatic compound and an acrylic acidcompound in the present of a palladium catalyst and a phosphine, whereinthe phosphine is a lipophilic, aliphatic phosphine of the formula I##STR6## in which R¹ at each occurrence independently of one another isstraight-chain or branched C₁₋₆ -alkyl, C₁₋₆ -alkoxy, C₄₋₈ -cycloalkylor C₄₋₈ -cycloalkoxy,R² is straight-chain or branched C₁₋₆ -alkyl, C₁₋₆-alkoxy, C₄₋₈ -cycloalkyl or C₄₋₈ -cycloalkoxy or a radical of theformula II ##STR7## in which R³ is divalent C₁₋₂₀ -alkylene, and R¹ isas defined above.
 2. A process according to claim 1, wherein thepalladium catalyst is a palladium compound in oxidation state 0 and/or+2 and is present in the reaction in a quantity of from 0.0001 to 1 mol%of palladium based on chloroaromatic compound.
 3. A process according toclaim 1, wherein the acrylic acid compound is of the formula (III)##STR8## in which R is CN or COR⁴, wherein R⁴ is OH, O--C₆ --C₁₀ -aryl,O--C₁ --C₂₀ -alkyl, NH₂, NH--C₆ --C₁₀ -aryl, NH--C₁ --C₂₀ -alkyl, N--C₆--C₁₀ -aryl, N--C₁ --C₂₀ -alkyl-C₆ --C₁₀ -aryl or N-di-C₁ --C₂₀ -alkyl,andR' is H, C₁ --C₁₀ -alkyl, C₆ --C₂₀ -aryl or R.
 4. A process accordingto claim 1, wherein the chloroaromatic compound is a chlorobenzene ofthe formula ##STR9## in which R⁵ is C₆ --C₁₀ -aryl, C₁₋₂₀ -alkyl, CN,S--R⁶, CO--OR⁶, --F, --OCF₃, OR⁶ or NR⁶ ₂ where R⁶ is hydrogen, C₆ --C₁₀-aryl or C₁₋₂₀ -alkyl,m is 0 or 1, n is 1 to 5, and n+m is 1 to 5,and amolar ratio of chloroaromatic compound to acrylic acid compound is inthe range from 1:0.7 to 1:3.
 5. A process according to claim 1, whereinthe reaction is carried out at temperatures in the range from 50° to180° C.
 6. A process according to claim 1, wherein the reaction iscarried out under a protective gas and with stirring.
 7. The process ofclaim 1, wherein each R¹ is independently branched C₃₋₆ -alkyl, C₃₋₆-alkoxy or cyclohexyl.
 8. The process of claim 3, wherein R in formula(III) is COR⁴ where R⁴ is O--C₁ --C₂₀ -alkyl.
 9. The process of claim 4,wherein R⁵ in formula (IV) is OR⁶ or NR⁶ where R⁶ is phenyl or C₁₋₁₀-alkyl, m is 0 and n is
 1. 10. The process of claim 1, wherein each ofthe R¹ radicals and the R² radical are identical and contain a branchedalkyl or alkoxy group or a cyclohexyl group.
 11. The process of claim 1,wherein the radicals R¹ are identical and R² is a radical of the formula(II) where R₃ is C₂₋₆ -alkylene.
 12. The process of claim 1, wherein themolar ratio of palladium:phosphine is from 1:0.8 to 1:2.5.
 13. Theprocess of claim 1, wherein the R² is a radical of the formula (II) andthe molar ratio of palladium:phosphine is from 1:0.4 to 1:1.25.
 14. Theprocess of claim 1, wherein the cinnamic acid compound prepared is2-ethylhexyl p-methoxycinnamate or isoamyl 4-methoxycinnamate.
 15. Theprocess of claim 1, wherein the reaction is carried out at a temperaturein the range of 80° to 150° C.
 16. The process of claim 1, wherein thereaction is conducted in the presence of a solvent.